7-103374422-T-G

Variant names:

• chr7-103374422-T-G
• rs200923483
• NM_198999.3:c.2212A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198999.3(SLC26A5):​c.2212A>C​(p.Thr738Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T738S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC26A5 NM_198999.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 0 publications found

Genes affected

SLC26A5 (HGNC:9359): (solute carrier family 26 member 5) This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

SLC26A5 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 61

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024808645).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198999.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A5	NM_198999.3	MANE Select	c.2212A>C	p.Thr738Pro	missense	Exon 20 of 20	NP_945350.1	P58743-1
	SLC26A5	NM_001167962.2		c.2116A>C	p.Thr706Pro	missense	Exon 19 of 19	NP_001161434.1	P58743-5
	SLC26A5	NM_206883.3		c.2041+2386A>C		intron	N/A	NP_996766.1	P58743-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A5	ENST00000306312.8	TSL:1 MANE Select	c.2212A>C	p.Thr738Pro	missense	Exon 20 of 20	ENSP00000304783.3	P58743-1
	SLC26A5	ENST00000393727.5	TSL:1	c.2218A>C	p.Thr740Pro	missense	Exon 18 of 18	ENSP00000377328.1	Q7Z7F4
	SLC26A5	ENST00000393723.2	TSL:1	c.2122A>C	p.Thr708Pro	missense	Exon 17 of 17	ENSP00000377324.1	P58743-6

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151732 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0119 AC: 2760 AN: 231186 AF XY: 0.00880

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.00360

Gnomad EAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0116

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00104 AC: 1504 AN: 1448234 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 745 AN XY: 719936

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00143 AC: 47 AN: 32932

American (AMR) AF: 0.00449 AC: 191 AN: 42540

Ashkenazi Jewish (ASJ) AF: 0.000309 AC: 8 AN: 25910

East Asian (EAS) AF: 0.00325 AC: 125 AN: 38482

South Asian (SAS) AF: 0.000258 AC: 22 AN: 85240

European-Finnish (FIN) AF: 0.0133 AC: 690 AN: 51904

Middle Eastern (MID) AF: 0.000467 AC: 2 AN: 4282

European-Non Finnish (NFE) AF: 0.000300 AC: 332 AN: 1107148

Other (OTH) AF: 0.00145 AC: 87 AN: 59796

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 2 AN: 151846 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74230

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67836

Other (OTH) AF: 0.00 AC: 0 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000209 Hom.: 0

ExAC AF: 0.0440 AC: 5340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0025	T
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.14	T
Polyphen		0.47	P
Vest4		0.26
MPC		0.41
ClinPred		0.018	T
GERP RS		4.3
Varity_R		0.17
gMVP		0.37
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200923483; hg19: chr7-103014869; COSMIC: COSV59701066;